JPS59118775A - Aralkyltriazole compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

The present invention relates to novel aralkyltriazole compounds and their salt-forming salts, processes for the preparation of these 16 compounds, and pharmaceutical formulations enriched with these compounds and their uses. In particular, the compound of the present invention has the following formula: (wherein, ph represents a phenyl group substituted with lower alkyl, a halogen atom and/or a trifluoromegal group, atk represents a lower alkylidene group, R4 represents a hydrogen atom, lower alkyl or lower alkoxy groups, or amine or carmoyl groups unsubstituted or substituted by acyl, lower alkyl or lower alkylene groups or by aza-, oxal- or thia-lower alkylene groups; R2 represents a carbamoyl group which is unsubstituted or substituted by an acyl, lower alkyl or lower alkylene group or by an azo-, oxa- or thia lower alkylene group, or R1 is unsubstituted or substituted by an acyl, lower alkyl or lower alkylene group; or when it represents an amine group substituted by an azo-, oxa- or thia-lower alkylene group, it represents a cyanide group, or R4 is unsubstituted or an amine group substituted by an acyl, lower alkyl or lower alkylene group, or an aza-, oxa- or 1-phenyl-lower alkyl-1, 2 represented by (1-phenyl-lower alkyl-1, 2)
, 3-1-IJ azole ratio compound. The phenyl radical ph contains, for example, up to 3, sometimes 2 or 1, of the above-mentioned substituents. optionally at the 3-, 4- or 6-position, preferably at the 3-, 4- or 6-position.
- or a phenyl group which may be further substituted with a lower alkyl group or a halogen atom at the 6-position,
represents a lower alkylidene group 2, R1 is a hydrogen atom,
A lower alkyl group, a lower alkoxy group, an amine group or a carbamoyl group which is unsubstituted or substituted with a lower alkyl group, and R2 represents a carbamoyl group which is unsubstituted or substituted with a lower alkyl group;
or 16 represents a cyan group when R1 represents an amine group which is unsubstituted or substituted with a lower alkyl group.
The present invention relates to compounds, methods for producing the same, and pharmaceutical preparations containing these metal compounds and their use. Amine groups which may optionally be substituted by acyl, lower alkyl, lower alkylene groups or by azo-, oxa- or thia-lower alkylene groups include, for example, amine groups, acyl fr+f which can be easily separated under physiological conditions. acylamino group, lower alkylamino group,
Represents a no-lower alkylamino group, a 5-spanning negative lower alkyleneamino group, or an azo-, oxa-, or thia-lower alkyleneamino group. Similarly, carbamoyl groups which may optionally be substituted with lower alkyl groups include, for example, carbamoyl groups, N-acylcarbamoyl groups having acyl groups that are easily separated under physiological conditions, N-lower alkyl Cal/S moyl group, N,N-lower alkylcarnogmoyl group or lower alkylene moiety or N,N-lower alkylene having 4 to 6 members in each of the aza, oxer or thia lower alkylene moieties; The acyl group that can be easily separated under physiological conditions in the O-acylamino group or N-acylcarbamoyl group, which is the N,N-(azo-, oxa- or thia)-lower alkylene-carnomoyl group, is In particular, it is a monosyl group of a lower alkanecarboxylic acid which may be substituted by a lower alkokene or a lower alkyl-1-hyamino group, an acyl group of a lower alkanesulfone, or an acyl group of an aliphatic half-ester or half-amide of carnones. Specifically, for example, lower alkanoyl groups such as formyl, acetyl, globionyl, butyryl, imbutyryl or pivaloyl groups, lower alkoxy-lower alkanoyl groups such as methoxy- or ethoxyacetyl groups, and lower alkylamino-lower alkanoyl groups such as N,N- trimethylglycyl group, lower alkanesulfonyl group such as methane- or ethanesulfonyl group, lower alkoxycarbonyl group such as methoxy-, ethoxy-, ingropoquine- or tert-butyloxycarbinyl group, ureido group, 3-lower alkylureto group, 3,3 -No lower alkylureido group or 3
, 3 - lower alkylene ureido group or 3. 3-(aza-, oxa- or thia)-lower alkyleneureido group. By "lower" organic groups and compounds herein are meant, throughout this specification, organic groups and compounds having 7, preferably 4 or less, carbon atoms. Lower alkyl groups are, for example, methyl, ethyl, glopyl,
It is a member of the pentyl, hexyl or hepnal group, including isopropyl, butyl, isobutyl, niguethyl or tertiary butyl groups as well as isomers. A halodane atom is a halogen atom of up to 35 atoms, such as, for example, a fluorine, chlorine or bromine atom. The lower alkylidene group is, for example, 1, having 4 or less carbon atoms,
1-Lower alkylidene groups, such as methylene, ethylidene, ], ]-glopylidene, 1,1-butylidene, but also lopylidene, 1,1-butylidene, Ul, 1--<butylidene, 1,1 -hexylidene or one member of the 1,1-hexylidene group. Low i alkoxy groups include methoxy, ethoxy, propoxy, isonoropoxy, butoxy, imbutoxy,
It is one of the inthyloxy, hexyloxy or hegetyloxy groups including sec-butoxy, tertiary-butoxy, or isomers. The lower alkylamino group in the lower alkylamino group and the 3-lower alkylureido group has, for example, 4 carbon atoms.
straight-chain lower alkylamino groups having up to 4 carbon atoms, such as methyl-, ethyl-, propyl- or butyl-amino groups; branched lower alkylamino groups having up to 4 carbon atoms, such as isopropyl-, ingtyl- or It is one of the methylamino group, methylamine, hexylamino, or heptylamino group. The no-lower alkylamino group in the no-lower alkylamino group and the 3,3-no-lower alkylureido group is, for example, a straight-chain so-lower alkylamino group in which each lower alkyl moiety has up to 4 carbon atoms, such as trimethylamino, diethylamino, diethylamino, It is a methylethylamino, sonorobylamino or butylamino group, but may also be a one-branched non-lower alkylamino group in which each lower alkyl moiety has up to 4 carbon atoms, such as a methylisonorobylamine group. 5- to 7-membered lower alkyleneamino groups or azo-, oxa- or thia lower alkyleneamine groups, as well as these groups as constituents of ureido groups, can be used, for example, as pyrrolitsuno, piperitno, piperazino, katsutake, e.g. N'- N/-lower alkylbiberazono, morpholino group or thiomorpholino group such as methylbiperasono. An N-lower alkylcarbamoyl group is a straight-chain N-lower alkylcarbamoyl group having up to 41 carbon atoms in the lower alkyl moiety, for example, N-methyl-1
N-ethyl-1N-noropyl- or N-butyl-carbamoyl radicals, but also branched N-lower alkylcarba7yl radicals having up to 4 carbon atoms in the lower alkyl moiety, such as N- Isopropyl, N-ingtyl-1N-sec-gtyl or N-tert-gtyl-carbamoyl group, 1fcu-'! It may also be one of the group consisting of butylcarpamoyl, hexylcarbamoyl or hebutylcarbamoyl. Examples of N,N-lower alkylcarbamoyl groups include linear N,N-lower alkylcarbamoyl groups in which each lower alkyl moiety has up to 4 carbon atoms, such as N,N-J methyl-1N, N-noethyl, N-ethyl-N-methyl-1N, N-kugropyru, or N,N-digtyl-carbamoyl, in addition to one branched group in which each lower alkyl moiety has up to 4 carbon atoms. N,N-lower alkylcarbamoyl groups such as N-isopropyl-N-methyl- or N-inbutyl-N-methyl-carbamoyl a
, 4& is N, N-Noventru, N. It may be one of the N-hexyl or N,N-hebutyl-carbamoyl groups. N,N1fi alkylene- or N,N~(azo-, oxa- or thia)-lower alkylene-carbamoyl radicals include, for example, pyrrolidinocarbonyl, pyrrolidinocarbonyl, piperanono or N'-lower alkylpiperazino, such as N' ~Methylbiwave lagladinocarbonylluphorinocarbonyl or thiomorpholinocarbonyl group. The acid salt compound of formula I is preferably a compound in which R1 represents an amide group substituted with an azo lower alkylene group, and/or a compound in which the cal-gumoyl group R4 and/or R2 represents such a group. A encounter that contains an amino group! Of course. Salts of such compounds, especially pharmaceutically acceptable acid addition salts with strong acids, may be considered. Salts of these strong acids include, for example, salts of inorganic acids, in particular halodane arsenic acid, especially salts with halodane folic acid or bromine folic acid, i.e. hydrohalides, in particular hydrochloride and hydrochloride; or salts of sulfuric acid, i.e. hydrogen sulfate and sulfur salts, and salts of suitable organic acids, such as nocarponates or organic sulfo/acid acids, such as maleates,
Fumarate, malate, tartrate or methanesulfonate as well as N-cyclohexylsulfamide [1
It is m. The new compound has certain mulberry-sedating properties, particularly a pronounced anticonvulsant action. This effect has a dosage range of approximately 3
0 to 30 OrlvAy (oral) as evidenced by clear metrazole resistance in mice. Sweet, the dosage range in mice and rats is approximately 10
~100 Q/K (M mouth) (mouse) and approx.
0・Evening/l! 9 (M) (rat), which is also evident in its significant protective effect against convulsions caused by electric shock. The compounds of formula I are therefore non-electroactively effective in the treatment of convulsions of various organs and are suitable, for example, for the treatment of epilepsy. Therefore, the compound of the present invention can be used as an active ingredient in an anticonvulsant drug or an antiepileptic drug. represents a phenyl group substituted with a methyl group, atk represents a lower alkylidene group, R4 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, an amine group, an acylamino group, N-lower alkyl-, N, N-no lower Alkyl-1N, N-lower alkylene- or N, N-(aza-, oxa- or thia)-lower alkylene-amino group, carbamoyl group, N
-acylcarbamoyl group or N-low M alkyl group 1N
, N-lower alkyl, N, N-lower alkylene, or N, N-(aza-, oxa- or thia)-lower alkylene-carno Z moyl group f: represents a carbamoyl group, N-acylcar/<moyl represents a group, N-lower alkyl, N, N-no-lower alkyl-1N, N-lower alkylene- or N, N-(aza-, oxa- or thia)-lower alkylene-carbamoyl group, or R is amine group, acylamino group, N-lower alkyl, N,N-di-lower alkyl-1N, N-lower alkylene- or N,N-(aza-, oxa- or thia)-lower alkylene-amine group: represents a cyano group, and R1 cacarbamoyl group, N
-acylcar/<moyl group, N-lower alkyl-, N,
When N-di-lower alkyl-1N, N-lower alkylene- or N,N-(aza-, oxa- or thia)-lower alkylene-carbamoyl group is represented, it represents a hydrogen atom or a lower alkyl group, provided that an acyl group is a lower alkanoyl group, a lower alkoxy-alkanoyl group, a lower alkylamino-honyl group, a lower alkoxycarbonyl group, a ureido group, with 7 carbon atoms in 1;
3-lower alkyl- or 3,3-no-lower alkylureido group, 3,3-lower alkyleneureido group mata means all 3,3-(aza-, oxa- or thea)-lower alkyleneureido groups, lower alkyl The lower alkyl group in the bercarbamoyl group and the N,N-di-lower alkyl-amino group in the bercarbamoyl group are, for example, carbon atoms. 7 or less, lower alkylene group or azo,
Oxa- or thia lower alkylene radicals relate, for example, to compounds having 4 to 6 ring members. The present invention particularly relates to ph in the formula l, for example, 2-halophenyl group, 2=)'J fluoromethylphenyl group, 2-lower alkylphenyl group, 2,3- or 2,6-cyhalophenyl group, 2-halo3- Lower alkylphenyl group or 3-halo 2-lower alkylphenyl group, 2-halo 6-low M furkylphenyl group, 2,3- or 2,6
-di-lower alkylphenyl group, 3-halo 2-)
IJ fluoromethylphenyl group or 2-halo 3
-trifluoromethylphenyl group or 2-halo 6-
It represents a trifluoromethylphenyl group, and atk is 1.
1-lower alkylidene group, R1 is a hydrogen atom, lower alkyl group, lower alkoxy group, amine group, lower alkylamino group, di-lower alkylamino group, carbamoyl group, N-lower alkyl/l/hamoyl group, or N,
represents an N-di-lower alkylcarbamoyl group, R2 is a carbamoyl group, an N-lower arykylcarbamoyl group, or
'vFiN, N-di-lower alkylcarbamoyl group, with the proviso that lower alkyl groups and N-lower alkylamino- or -carbamoyl groups and lower alkyl groups of N,N-no-lower alkylamino- or -carbamoyl groups; The radicals, especially lower alkoxy and lower alkylidene, relate, for example, to compounds having up to 7 carbon atoms. The present invention particularly relates to phenyl groups in formula I in which pH is a lower alkyl group or a phenyl group substituted with up to 3 halogen atoms and/or a trifluoromethyl group, provided that the lower alkyl group has up to 4 carbon atoms, e.g. a methyl group, and the halogen atom has an atomic number below 35, i.e. a fluorine, chlorine or bromine atom), such as a 2-lower alkylphenyl group, a 2-also L<U3-halophenyl group,
2-trifluoromethylphenyl group, 2,3-4 or 2,6-di-lower alkylphenyl group or 2,3-1
2.4- or 2,6-dino-10 phenyl group, atk having up to 4 carbon atoms, 1,1-lower alkylidene group, such as methylene group, ethylidene group or 1
, 1-propyIJ f" y group, R1 is an amine group, a lower alkanoylamino group having up to 7 carbon atoms, a lower alkylamino group in which each alkyl moiety has up to 4 carbon atoms, or N-lower alkanoylcarpamoyl, which represents a lower alkylamino group, for example an acetylamino group, a methyl-, ethyl- or propyl-amino group, a dimethyl- or diethyl-amino group, and R2 is a carbamoyl group, having up to 7 carbon atoms 2 swords, N-lower alkyl-, N,N-di-lower alkyl-mayu is N,N-lower alkylene-carbamoyl group (7
(wherein each lower alkyl moiety has 4 carbon atoms and the lower alkylene moiety contains 4 to 6 ring members), such as carbamoyl, N-acetylcarnomoyl, N-methylcarbamoyl. , N,N-dimethylcarbamoyl or piperidinocarbonyl, or a cyanogen group. The present invention particularly provides that the lower alkyl substituent in ph in formula (1) is a lower alkyl group having not more than 4 carbon atoms, such as a methyl or ethyl group, and the halogen substituent in Ph is a halodane atom having an atomic number of not more than 35, such as a chlorine atom. So,
1, pH is 2-halophenyl group e.g. 2-fluoro-1
2-Chloro-modi, 2-bromo-phenyl group, 2-trifluoromef/L/phenyl group, 2-lower alkylphenyl group (e.g. 2-methyl- or 2-ethylphenyl group) 2.3- or 2, 6-cyhalophenyl group such as 2,6-nochlorophenyl group or 2,3- or ha2,6-no lower alkylphenyl group such as 2.3
-represents a trimethylphenyl group, and atk is a 1.1-lower alkylidene group having not more than - carbon atoms, such as a methylene group,
represents an ethylidene group or a 1,1-glopylidene group,
R1 represents an amine group or a lower alkylamino group or di-lower alkylamino group having up to 4 carbon atoms, such as a methyl-, ethyl- or propyl-amino group, trimethyl- or diethyl-amino group, and R2 represents a carbamoyl or a cyano group. The invention particularly relates to the compounds described in the Examples. The compound represented by the formula I can be prepared, for example, by converting the azide represented by the secondary formula (2): Ph -hlk -Ns (1) into the following formula (2): 2 Y3 (in the above formula, R' is cyano represents a carbamoyl group unsubstituted or substituted by an acyl, lower alkyl or lower alkylene group or by an aza-, oxer or thia-lower alkylene group, and Y represents an amine group substituted with the above group; , or R
When 2' represents a carbamoyl group which is unsubstituted or substituted by an acyl, lower alkyl or lower alkylene group or by an azo-, oxa- or thia-lower alkylene group, it is a hydrogen atom, a lower alkyl group, a lower alkoxy group or fC/l′i represents a carbamoyl group, unsubstituted or substituted with the aforementioned groups, Y2 and Y3 together represent another bond, or R2′ is a cyan group or an unsubstituted or acyl group; represents a carbamoyl group polysubstituted by a lower alkyl or lower alkylene group or by an aza-, oxa- or thia-lower alkylene group, Y and Y2 together represent an imino group, and Y represents a hydrogen atom; (representing the formula
The isomer of the formula is isolated and, if desired, the compound obtained in this way is converted into a different compound of the formula (1). The tautomer of the compound represented by 2m is the formula of a ketimine compound in which Y and Y2 represent an imino group and Y3 represents a hydrogen atom: 1'eC-CH2-R2'(I
[Ia) is a cyanoacetyl tautomer. The salt of the compound 2) is, for example, a compound in which Y and Y2 in formula m together represent an imino group and Y3 represents a hydrogen atom, or an alkali metal salt of the tautomer thereof represented by formula 111a. It is a metal salt such as This reaction is carried out in a conventional manner, preferably in an inert solvent.
If necessary, it is carried out in the presence of a condensing agent and/or at elevated temperature. Examples of inert solvents include aromatic or araliphatic hydrocarbons such as benzene or toluene or ethers such as tert-butoxymethane, tetrahydrofuran or dioxane, and also those of formula 1
For reaction with compounds 11a, alcohols such as lower vulcanols such as methanol, ethanol or butanol are used. A condensing agent, for example, for the reaction with a compound of formula m in which Y1 and Y together represent an imino group and Y3 represents a hydrogen atom or its tautomer of formula 1[1a] is a salt-forming agent. Condensing agents such as metal alcoholades such as sodium methoxide, sodium ethoxide, or other alkali metal lower alkoxides, metal amides such as sodium amide, lithium diinzolobylamide, etc., or organometallic compounds such as lower alkylmagnesium halides or lower alkyllithium compounds. , specifically methyl- or butyl-
Magnesium bromide or butyl lithium. Instead of carrying out the reaction in the presence of one of the precondensing agents, it is also possible to use either the components of formula IIl or Pa in the form of a salt. In a preferred embodiment of this method, for example, an azide represented by 2 (2) and a compound in which Y represents a hydrogen atom or a lower alkyl group and Y and Y3 represent another bond are mixed in benzene or dioxane to approximately The reaction is carried out at 60-120°C, preferably at boiling temperature, or the compound of composition a is reacted at about 40-100°C, preferably at boiling temperature, in the presence of sodium methoxide or sodium ethoxide and methanol or ethanol as solvents, respectively. That's true. Several starting materials of the formula (1) and some starting materials of the formula (2) are known. The new starting material of the formula (III) can be prepared in a manner similar to that of known starting materials, for example Ph-atk-X (IV), where X is a reactive esterified hydroxy group, e.g. chlorine, bromine. or iodine, or sulfonyloxy group, e.g. lower alkanesulfonyloxy group, optionally substituted benzenesulfo=/l/oxy group, t hamethane-, ethane-, benzene-1p-)/l/ene-1. <
Hp-bromobenzene-sulfonyloxy group or fluorosulfonyloxy group. ] with an alkali metal azide such as sodium azide,
For example, by reacting in dimethyl sulfoxide or dimethylbormamide, or by reacting an alcohol of formula (1) (in formula (2) with an It is obtained by reacting with hydrogen, for example dissolved in toluene. The new compound can also be produced, for example, by the following secondary formula ■: Ph -atk -Z (IV) (wherein,
2 represents a reactive esterified hydroxyl group. ) is reacted with an IH-1,2,3-triazole derivative represented by the following formula (1) or a salt thereof, and if necessary, the resulting isomer mixture is separated into all components, and the compound represented by the formula The isomer represented by (2) is isolated, and the compound obtained in this manner is converted into another compound represented by the formula (2) as desired. The reactive esterified hydroxyl group 2 is, for example, chlorine,
halogen atoms such as bromine or iodine, or sulfonyloxy groups such as lower alkanesulfonyloxy groups, optionally substituted benzenesulfonyloxy groups such as methane-, ethane-, benzene, p-)luene-I, (Idp-bromo The benzene-sulfonyloxy group is a fluorosulfonyloxy group. Salts of the compound of formula (1) are, for example, alkali metal salts or alkaline earth metal salts, such as sodium, potassium or calcium salts. The reaction is carried out in the usual manner. by a method, for example in the presence of a basic condensing agent or using a component of the formula ■, advantageously in the form of a salt,
This is preferably carried out in a solvent or diluent, with heating if necessary. The basic condensing agent is, for example, a basic condensing agent that forms a salt with the component represented by the formula (2), specifically an alkali group IJ alcoholade, such as sodium methoxide or sodium ethoxide, an alkali metal or alkaline earth metal amide, etc. Sodium amide or lithium diisonorobyl amide. As mentioned above, the component represented by formula (1) is preferably converted in advance into one of its salts, for example by reaction with one of the bases mentioned above. The solvent for carrying out the reaction in the presence of an alcoholade is preferably an alcohol, and the solvent for carrying out the reaction in the presence of an amide is, for example, a neutral organic solvent such as a lower alkyl amide of phosphoric acid or a lower alkyl sulfoxide such as a lower alkyl sulfoxide. Hexamethyl phosphate triamide or trimethyl sulfoxide, respectively. In this method, amino group R1 or carbamoyl group R
The amine group as a component of 2 is at least N-mono-directly substituted, preferably N,N-no-substituted, i.e. acylamino group, lower alkylamino group-1: or preferably di-lower alkylamino group, lower alkylene group. It is particularly suitable for preparing compounds with amino groups or (N'-lower alkyl) aza-, oxer or ther lower alkylene amino groups. The starting materials of the formulas (1) and (2) which are not known in this invention are prepared by conventional methods. That is, the compound represented by 2) can be prepared, for example, by reactive esterification of the corresponding alcohol represented by formula can get. The compound represented by the formula (2) is prepared as follows: Hydrogen azide or trimethylsilyl azide is converted into the following formula (2Y3) (wherein R2' is a cyano group, unsubstituted or unsubstituted, acyl, lower alkyl, or lower alkylene). Yl represents a cargumoyl group substituted by aza-, oxa- or thia-lower alkylene group; Yl represents an amine group disubstituted by the aforementioned groups;
' is a hydrogen atom, a lower alkyl group, a lower alkoxy group or an unsubstituted carbamoyl group substituted by an acyl lower alkyl or lower alkylene group or by an aza-, oxa- or thia-lower alkylene group; or represents a carbamoyl group substituted with the aforementioned groups, Y2 and Y3 taken together represent another bond, or R2' is a cyano group or unsubstituted or substituted by an acyl, lower alkyl or lower alkylene group or aza- , represents a carbamoyl group di-substituted by an oxa- or thia lower alkylene group, Yl and Y2 together represent an imino group, and Y
3 represents all hydrogen atoms. ) or a tautomer thereof and/or a salt thereof, and optionally 1-trimethylsilyl thus obtained)
Amino group R and/or carbamoyl group R2 in IJ azole derivatives are acylated, lower alkylated or disubstituted with lower alkylene groups or with aza-, oxa- or thia lower alkylene groups, followed by mild hydrolysis of the trimethylsilyl group. Excluded by doing so. The novel compound can also be prepared as follows:
, a group, or Y4 represents an R2 group and Y5 is Y. represents a group, where YA is a group that can be converted into an unsubstituted or substituted carmoyl group as described above, or Y
When 5 represents an optionally substituted amino group R1, it represents a group that can be converted to a cyano group, and YB represents an optionally substituted amino group R1, which may be optionally substituted as described above. A group that can be converted into a moyl group. ) or a salt thereof, in which YA is converted into an all-cyano group or optionally substituted as mentioned above, and/or YB is converted into a carboxymoyl group which may be optionally substituted as mentioned above. converted to a cal-gumoyl group which may be substituted with,
If necessary, divide the resulting isomer mixture into each component [t L
, the isomer of formula (1) is isolated and, if desired, the compound obtained in this way is converted into another compound of formula (I). The groups YA and YB according to the above definitions can be, for example, free carboxyl groups or carboxylic groups of salts or anhydrides, optionally by N-lower alkylated or lower alkylene or by ab-, oxa- or thia-lower alkylene groups. N,N-disubstituted ami, dino group or esterified cardexyl group. The group YB is also a cyan group. Esterified carboxyl groups include, for example, lower alkanols, carboxyl groups esterified with lower alkyl mercaptans, ie lower alkoxy- or lower alkylthio-cals, but also other alcohol captans, e.g. It may be esterified with a phenol or thiophenol substituted by . Carboxyl groups in the form of salts include, for example, ammonia or mono- or di-lower alkyl amine carboxyl groups, or carboxyl groups present in the form of metal salts, such as alkali metal or alkaline earth metal salts. Carboxyl groups in the anhydride form are, for example, carboxyl groups in the form of halides, such as the chlorocarbonyl group, but may also be anhydrified with reactive carboxylic acids, such as the alkoxycarbonyloxycarbunyl group or the trifluoroacetoxy group. Represents a carbonyl group. Amidino groups optionally lower alkylated or dino-substituted by lower alkylene groups or aza-, oxa- or thia-lower alkylene groups include, for example, unsubstituted amidino groups, N-mono-, N, N- or an N,N'-di-lower alkylated amidino group or a lower alkylene group or an N,N-disubstituted amidino group by an azo-, oxa-, or thia-lower alkylene group. The conversion of the group Y4 mentioned above into a cyano group or a carbamoyl group optionally substituted as above or the conversion of the group Y5 into a carbamoyl group optionally substituted as above can be carried out by conventional methods. , carboxyl groups in free, esterified or anhydride form as starting materials and optionally 5N
-lower alkylated or lower alkylene group or aza-, oxer or thia by lower alkylene group
, N-disubstituted amidino groups are used to perform solvolysis, i.e., hydrolysis or hydrolysis or amitrilysis (
The reaction is carried out with ammonia or mono- or di-lower alkylamines, lower alkyleneamines or aza-, oxa- or thia-lower alkyleneamines). By hydrolysis, for example, optionally lower alkylated or N,N-disubstituted amidino groups Y4 and/or Y5 by lower alkylene groups or by aza-, oxa- or thia lower alkylene groups are optionally substituted with corresponding groups. The cyan group Y5 is converted into a carbamoyl group. Hydrolysis can be carried out, for example, with mineral acids, sulfonic acids or carboxylic acids, in particular sulfuric acid, phosphoric acid, hydrochloric acid or other hydrohalic acids, p-toluenesulfonic acid or other organic sulfonic acids or lower alkanoic acids such as acetic acid. It is carried out in the presence of an acidic hydrolyzing agent such as, preferably in a catalytic amount. Aminolysis magco converts, for example, a free carboxyl group into a xyl group ti into a salt form or an esterified carboxyl group into an unsubstituted or substituted carboxyl group as described above. The operation is preferably carried out in an inert solvent, if necessary in the presence of a condensing agent. If the anhydride carboxyl radical is used as the starting material, the condensing agent can be, for example, an alkali metal hydroxide or carbonate, '=
! or an excess amount of an organic nitrogen base, such as an amine, corresponding to the amine groups to be introduced, -! or a tertiary organic nitrogen base such as a tri-lower alkylamine or a tertiary heteroaromatic nitrogen base such as triethylamine or pyridine;
Also, when using an esterified carboxyl group as the starting material, the acidic condensing agent is an inorganic acid such as, for example, hydrohalic acid. Free carboxyl groups can be converted into optionally lower alkylated carbamoyl groups, for example by heating the ammonium salt formed as an intermediate or by adding a dehydrogenating agent such as an acid anhydride such as phosphorus pentoxide or acetyl chloride or a carbodiimide. For example, N,
Dehydrogenation occurs through the action of N'-dicyclohexylcarbodiimide. All known starting materials represented by the formula (2) are prepared by the conventional method as follows: The azide represented by the following formula (2): ph -atk -N3 (II) is converted into the azide represented by the following formula (2): 2Y3 (wherein Yl represents a group Y5, Y2 and Y3 represent another bond, or Yl represents a hydrogen atom or a lower alkyl group, Y2 represents a hydrogen atom, Y3 represents a hydrogen atom, Alternatively, Yl and Y2 both represent an imino group, and Y3 represents a hydrogen atom.) and the tautomer and/or salt of this compound, for example, React as described for the reaction. A starting material in which Y5 represents a lower alkoxy group and Y4 represents a YA group in the formula (1) can be produced, for example, as follows: an azide represented by the formula (2) is converted to the azide of the formula: HOOC-CH2-YA (
5-hydroxy-1 produced by reacting an acid represented by XI) or an ester thereof, such as a lower alkyl ester, such as a malonic acid di-lower alkyl ester and/or a salt thereof, preferably in the presence of an alkali metal alkoxide. -Ph -atk-4-Y -IH-1, 2, 3
The hydroxyl groups in the -triazole are preferably lower alkylated by reacting with a reactive lower alkyl ester such as trimethyl sulfate in the presence of sodium hydroxide. The new compound is obtained by eliminating H-Y6'i from a compound represented by the following formula (1): (wherein Y6 represents a leaving group), and if necessary, separating the resulting isomer mixture into each component. and isolating the isomer of formula I and optionally converting the compound obtained in this way to another compound of formula I. The leaving group Y6 is, for example, a hydroxyl group, and the lower alkoxy group 1L is an optionally substituted amine group, and the lower alkoxy group is preferably the same as the lower alkoxy group R1, and the optionally substituted amine group is a free or is preferably the same as the substituted amine group R1. The elimination of H-Y6 generally occurs naturally in two individual cases:
applying thermal energy or acidic or basic agents such as inorganic acids such as sulfuric acid or hydrochloric acid or caldicic or sulfonic acids such as acetic acid or p-1 luenesulfonic acid, or alkali metal hydroxides or sodium methoxide. Alkali metal alcohols such as
It is advantageous to have a tiger present. The starting material represented by the formula ■ is, for example, the following formula ■: ph −
atk -N5(n) A compound represented by the following formula represents a carbamoyl group substituted by
'(H, Y3 represents a hydrogen atom, Y7 and Y
8 represents another bond or Yl, Y2 and Y7
represents a lower alkoxy group, Y3 and Y8 are hydrogen atoms, or Y and Y2 together represent an oxo group, Y7 represents a hydrogen atom or a lower alkyl group, and Y3 and Y8 are hydrogen atoms. represents. ) or its tautomer and/or salt, specifically the following formula: Y'-C(=0)-CH2-R
2' (X, : Y,'-hydrogen atom or lower alkyl group), Yl-C(Y2)=CH-R2' (xb:
Yl and Y2 = lower alkoxy group, or amine group independently of each other, unsubstituted or substituted as indicated by R1), or Yl-C(Y2) (Y7)-CH
It is preferably produced in situ by reacting with 2-R2' (Xc: Yl. Y and Y, = lower alkoxy group) and can be used in another reaction without isolation. Compounds of formula I in which R1 in formula I represents a lower alkoxy group can also be prepared as follows: and, if necessary, separating the resulting isomer mixture into its components and isolating the isomer of formula I,
If desired, the compounds obtained in this way are converted into different compounds of formula I. To convert a hydroxyl group into a lower alkoxy group, for example, a reactive lower alkyl ester, such as a hydrohalic acid ester, in particular an ester of hydrochloric acid, hydrobromic acid or hydroiodic acid, a sulfuric acid ester, or di-lower alkyl sulfates, or sulfonic acid esters, such as (1-alkane- or optionally substituted benzene-, with a lower alkanol, preferably with a basic agent such as an alkali metal hydroxide, carbonate or alcoholade, in particular hydroxide), potassium or potassium carbonate, potassium carbonate or sodium methoxide or a tertiary organic nitrogen. This is carried out by reaction in the presence of a base such as a tri-lower alkylamine such as triethylamine or pyridine. The starting material represented by Nikari is, for example, the following formula ■: Ph −
an azide represented by atk -N3 (II) with an acid of the formula: HOOC-CH2-R2 or an ester thereof, such as a lower alkyl ester;
It is prepared by reacting as indicated for reaction with a compound of formula III a. The compound obtained by this method is represented by the general formula I.
Conversion to other compounds of formula I can be achieved by converting more than one variant compound into different variant compounds. The cyano group R2 can be hydrolyzed, for example, under basic conditions, specifically in the presence of an alkali metal hydroxide, to form a carbamoyl group. The cyan group can also be produced by first treating the nitrile represented by formula 1 with, for example, a lower alkanol, phenol or other alcohol to form an imino ether, and then reacting this imino ether with a 7- or di-lower alkyl amine. The aminone can be converted into an N-lower alkyl- or N,N-no-lower alkyl-carbamoyl group by hydrolyzing the aminone, preferably under mildly acidic conditions. On the contrary, the carbamoyl group R2 forms a cyano group upon dehydrogenation. For example, dehydrogenating agents such as acid anhydrides such as phosphorus pentachloride or phosphorus oxychloride, cyclic silazane'=! The reaction mixture is reacted with dichlorocarpene or trichloromethane in the presence of about 40% sodium hydroxide solution and a phase transfer catalyst such as benzyltrimethylammonium chloride. Furthermore, the -level amino group R1 can be converted into an acylamino group, a heptano or no lower alkylamino group or a lower alkyleneamino group, an aza-, oxa- or thia lower alkyleneamino group, and a mono-lower alkylamino group R1 can be converted to no lower alkylamino group. Acylation can be carried out, for example, using a modified acid anhydride or chloride such as acetic anhydride, a mixed anhydride of formic acid and acetic acid, a chloro- or bromoformic acid lower alkyl ester, methanesulfonyl chloride, dimethylcarbamoyl chloride, and if necessary a base. For example, it is carried out in the presence of triethylamine or pyridine or with inorganic acids such as sulfuric acid. Alkyl (alkylene)
Reactive esters of lower alkanols, lower alkanediols, aza-, oxa- or thia-lower alkanediols, such as lower alkyl (alkenedi) halides such as bromides, lower alkyl (alkene)-sulfonates such as methanesulfonate. or p-) luenesulfonate or a di-lower alkyl sulfate, preferably under basic conditions, e.g. Promid fc is carried out in the presence of benzyltrimethylammonium chloride. In exactly the same way, the carbamoyl groups R2 and /mak are R1'eN-acylcarbamoyl groups, N-mono- or N,N-no lower acylcarbamoyl groups sweet or N
, N-lower alkylenecarbamoyl group or N, N-(
It can be converted into an aza-, oxa- or thia)-lower alkylenecarbamoyl group, and the N-mono-lower alkylcarpamoyl # group 1d' N , N -c can be converted into a lower R alkylcarbamoyl group. In this case, strong basic condensing agents such as alkali metal amide or alcoholades such as sodium amide or sodium methoxide are required. Depending on the starting materials and the method, novel compounds can be prepared, for example, with R1
and exists in the form of one of the possible isomers at the position of R2, or in the form of a mixture thereof. Depending on the number of asymmetric carbon atoms, the novel compounds can also exist in the form of optical isomers, e.g.
m1xture). The resulting regioisomeric mixtures, norastereomeric mixtures and racemic mixtures, can be prepared by known methods, for example by chromatography and/or fractional crystallization, taking advantage of the differences in physical and chemical properties between each component, respectively. Separation into pure regioisomers, diastereomers and racemates. The racemic compound obtained is also
The optical antipodes are separated by known methods. As a method,
Then, the racemic product can be obtained by recrystallization, e.g. from an optically active solvent with the help of organic microorganisms, or by reacting an acidic precursor (Y4 and/or Y5-carboxyl group), e.g. forming an ester with an acid, and separating the ester obtained in this way into noastereomers, for example by exploiting the difference in their solubility;
From this, a method is used in which the entire enantiomer is released by the action of an appropriate drug. Advantageously, the more active of the two enantiomers is isolated. The racemic compound of the salt-forming compound represented by formula I below can be reacted with an optically active auxiliary compound to form a diastereomer mixture, specifically, a noastereomer acid addition salt by reacting with an optically active acid. This acid addition salt is separated to give diastereomers, which can be resolved by liberating the respective enantiomers according to conventional methods. Optically active acids commonly used for this purpose are, for example, D-
Or L-tartaric acid, di-0-toluyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, or quinic acid. Furthermore, the obtained free salt-forming compound can be prepared by a known method.
For example, the free compound can be converted into an acid addition salt by reacting a solution of the free compound in a suitable solvent or solvent mixture with one of the acids mentioned above or with a suitable anion exchanger. The acid addition salt obtained is converted to the free compound by known methods, for example by treatment with a base such as an alkali metal hydroxide, metal carbonate or bicarbonate or ammonia or by treatment with a suitable anion exchanger. sell. The acid addition salts obtained can be prepared by treating, for example, a salt of an organic acid with a suitable metal salt of the acid, such as a sodium, barium or silver salt, in a suitable solvent, so that the resulting organic salt is insoluble. By separating it from the reaction mixture, it can be converted into another acid addition salt. Compounds containing these salts can also be obtained in the form of hydrates, and may also contain the solvent used for crystallization. Since the relationship between the free novel compound and its salt is very close, it is appropriate and convenient to understand that throughout this specification the free compound or its salt includes the corresponding salt as well as the free compound, as the case may be. The present invention does not require that the compounds obtained as intermediates be used as starting materials in every step of the process to carry out the remaining steps, or that the starting materials are used in the form of salts or produced in particular under reaction conditions. Embodiments of the method. That is, all intermediates of formula (1) are formed according to a modified method of reaction of compounds of formula (2) and X and can be further reacted without isolation. The present invention also leads to new starting materials of formula 11, V, Vl, IX and Kari which have been specifically developed for the preparation of the compounds of the invention, in particular compounds of formula I which have been initially characterized as preferred. Concerns a series of starting materials, their preparation and their use as intermediates. The compounds of formula I are suitable for enteral, e.g. oral, or parenteral administration, e.g. containing a therapeutically effective amount of the active ingredient, optionally together with an inorganic or organic solid or liquid pharmaceutically acceptable carrier. Used as a pharmaceutical preparation. That is, tablets or gelatin capsules are
Together with the active ingredient, diluents such as lactose, dextrose, sucrose, mannitol, nrubitol, cellulose and/or glycine, and/or lubricants such as silica, talc, stearic acid or its salts, such as magnesium stearate or stearate. Those containing calcium phosphate and/or polyethylene glycol are used. The tablets may also contain binders such as magnesium aluminum silicate, powders such as sorghum, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and 7-ounce polyvinylpyrrolidone, and optionally disintegrants such as starch, Agar, alginic acid or its salts such as sodium alginate,
and/or foaming agent mixtures, which may also contain adsorbents, dyes, flavors and sweeteners. Furthermore, the novel compound of formula (2) can be used in a formulation for parenteral administration or in the form of an infusion solution. Such solutions are preferably isotonic water bath solutions or suspensions, for example in the case of lyophilized formulations containing the active ingredient alone together with a carrier such as mannitol, prepared before use. be able to. The pharmaceutical preparations are sterilized and/or contain additives such as preservatives, stabilizers, wetting agents and/or emulsifiers,
It may also contain a solubilizing agent, an osmotic pressure adjusting agent or a buffering agent. The pharmaceutical preparations according to the invention may optionally contain further pharmacologically active substances, which are prepared by known methods, for example using conventional mixing, granulating, sugar-coating, dissolving or dry-freezing methods. Ru. The pharmaceutical preparation of the present invention has an active ingredient of about 0.1
- to 100 inches, particularly about 1 inch to about 50%, up to 100 inches when dried and frozen. The present invention still relates to the use of compounds of formula I, in particular their use in pharmaceutical formulation forms. The amount administered depends on various factors, such as the method of administration, and race, age and/or individual condition. The daily dose for oral administration is between about 5 mV'1 Kg and about 50 mg/Iq, about 0.5 k for a warm-blooded animal weighing about 70 kg.
l? and about 5.0 g. The invention is illustrated by the following examples; in the examples, temperatures are in degrees Celsius. Example 1 Sodium 23.9 (1 mol) Ethyl alcohol 11
101 g (1.2 mol) of cyanoacetamide dissolved in
Add to this. O-chlorobenzyl azide 167.5
g (1 mol) are added to this suspension at 40-45° and the whole is heated under reflux for 2 hours. After cooling to 30°, water 1001
00O is added and the precipitated product is filtered off with suction and then washed several times with warm water. When recrystallized from nooxane and toluene,
5-amino- colorless crystals with melting point 206-207°
1-(o-ri00benzyl')-1H-1,2,3-triazole-4-cargoxyamide is obtained. Example 2 In a similar manner, using E7 with 2,6-dichloropenzyl azide as the starting material, amino-1-(2,6-dichlorobenzyl)-11(-1,2,3-triazole-
4-carpoxyamide is obtained, this compound has a melting point of 24
3 to 245° (recrystallized from methanol), the starting material is prepared, for example, as follows: nomethyl sulfoxide 50 m/? 24 g (0.1 mol) of 2,6-dichlorobennorpromide dissolved in the solution were added to a solution of 7.2.9 (0.11 mol) sodium azide suspended in 50 mJ of dimethyl sulfoxide at room temperature. and the whole is stirred at room temperature for 2 hours. The mixture is diluted with water and extracted with cyclohexane. Wash the organic phase several times with water. After drying with sodium sulfate, the cyclohexane was distilled off under reduced pressure at 50°. Colorless liquid 2,6-cyclobenzyl azide is obtained. This is used without further purification. Example 3 In the same manner as in Example 2, using 0-methylbenzyl chloride as a starting material, 5-amino-1-(o-methylbenzyl)-1H-1,
2,3-) Riazole-4-carboxamide is obtained. It has a melting point of 227-228° (recrystallized from dioxane/ethanol). Example 4 In the same manner as in Example 1, starting materials and

Using 0-fluoropentuluazide at [-, 5-amino-1-(0
-fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide is obtained. This has a melting point of 19
8-190° (from methanol). Example 5 Using 0-promopenzyl azide as the starting material in the same manner as in Example 1, 5-amine-1-(0-bromobenzyl)-1H-1,2,3-)riazole -4
- carboxamide is obtained, which has a melting point of 211-21
3° (from ethanol). Example 6 In the same manner as in Example 1, 1 was used as the starting material. -When trifluoromethylbenzyl azide is used, the amino-
1-(o-trifluoromethylbenzyl)-1H-'1
．． 2.3-Triazole-4-carboxamide is obtained, which has a melting point of 197-198° (from methanol). The starting material is prepared, for example, as follows: first,
Masodicarboxylic acid diethyl ester 17.4 g (0,
A solution of 50 ml of toluene containing 1 mole of
1 solution and then 1 CO-) of hydrazinic acid in 120 ml of 5-100 ml solution.
'J fluoromethylbenzyl alcohol 17.6 g
(0.1 mol) is added to the mixed solution. The whole is stirred at room temperature for 2 hours. The precipitated hydrazinodicarboxylic acid ester is filtered off with suction, the toluene solution is concentrated by evaporation, and the residue is treated with cyclohexane. The entire cyclohexane solution is decanted to separate it from impurities, filtered through a small amount of silica gel and then evaporated under reduced pressure at 500 ml. This is a colorless liquid. -trifluoromethylbenzyl azide is obtained. Example 7 By the same method as in Example 6, using 2,3-dimethylbenzyl alcohol as a starting material, 5-amino-1-(2,3-
Dimethylbenzyl)-1H-1,2,3-triazole-4-carboxamide is obtained. This has a melting point of 217
~219° (from ethyl acetate). Example 8 By the same method as in Example 2, 1-(o
-chlorophenyl)-phenethyl chloride,
5- via 1-(o-chlorophenyl)-ethyl azide
amino-1-[1-(o-chlorophenyl)-ethyl)
-1H-1,2,3-triazole-4-carboxamide is obtained: melting point 202-204° (from ethanol) Example 9 By a method similar to Example 2, 1-(o
-chlorophenyl)-zorobyl chloride,! :
, 1-(o-chlorophenyl)-zorobylazidora, 5-amino-1-(1-(o-rioophenyl)-propyl]-1H-1,2,3-)lyazole-4-carboxamide can get:? Melting point 152-153° (from ethanol) Example 10 Using a method similar to Example 6, 1-(o
-chlorophenyl)-butanol gives 1-(
5-amino-1-[1-(0-chlorophenyl)-butyl]-LH via o-chlorophenyl)-butyl azide
-1.2.3-triazo→re-4-carboxamide is obtained: melting point 150-152° (from methanol) Example 11 5-amino-1-(o-chlorobenzyl)-1H-1,
25.2 g of 2,3-) lyazole-carboxamide (
30.6 mol) of phosphorus oxychloride was dissolved in 100° of dimethylformamide and stirred at 0°.
! li' (0.2 mol) is added dropwise. The whole is then rapidly heated until the reaction mixture reaches 80° and is immediately cooled again to 20°. At this temperature, IN hydrochloric acid 100
- is added dropwise, the whole is rapidly heated and reflux is continued for 5 minutes. The heated reaction solution is diluted with 400 g of water and the precipitated product is filtered off with suction. After washing with water several times, recrystallization from ethyl alcohol yields 5-amino-1-(0-chlorohensyl)-1H-1,2,3-)liagur-4-carboxylic acid nitrile with a melting point of 174-176°. Example 12 5-Amino-1-(o
-Chlorobenol)-1H-1,2,3-)lyazole-4-carboxylic acid nitrile 11.7.9 (0.05 mol) and methyl iodide 21.3.9 (0.15 mol) solution , acetonate) 11.2 g of powdered potassium hydroxide and 1.6 g of tetrabutylammonium bromide in 100 ηl of IJ. 9 (0,005 mol) was added dropwise at 20 to 25° to a stirred and suspended solution. After 1 hour, the inorganic material is decanted off and the acetonitrile is evaporated off under reduced pressure. The residue 7 is dissolved in ethyl ether, the insoluble materials are removed, and the ether solution is filtered through a silica shell. Evaporating the ether gives 1-(o
-chlorobenzitree 5-dimethylamine-IH-1. 2.3-) IJ azole-4-carboxylic acid nitrile is obtained: melting point 64-67°. Example 13 30% strong hydrogen peroxide solution 251n1. ethanol 30
0 mg and 1- in 25 portions of 5N sodium hydroxide solution.
(o-chlorohenge/l/) -5-dimethylamino-
Add 40~ to the solution in which LH-1,2,3-triazole-4-carginic acid nitrile 13.1.9 (005 mol) is dissolved.
Add dropwise at 50°. After the addition is completed, the whole is heated to 40-50°.
Stir for 2 hours, dilute with 600 ml of water and filter the precipitated product with suction. After washing with water and crystallizing in 70% strong ethanol, 1-(o-chlorobenzyl)-5
-tumethylamino-IH-L2,3-triazole-4
- Carboxamide is obtained: melting point 164-166°
. Example 14 1-(o-chlorobennor)-LH-1,2,3-triazole 4,5-dicarboxylic acid trimethyl ester 939
(0.03 mol) dissolved in 250 ml of methanol,
Saturate with ammonia at 50°. After standing for 3 days at 60°, the reaction solution is cooled and the crystallized product is filtered off with suction and washed with methanol. This results in 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4,5
- Socarboxamide is obtained: melting point 222-224
°. The starting material is prepared as follows; benzene 25m
1 to acetylenenocarzenate dimethyl ester 8.9
(0,054 mol) was added dropwise to a refluxing boiling solution of 8.4 g (0.05 mol) of O-chlorobenzyl azide dissolved in 50 d of benzene. After continuing to reflux for an additional hour, The whole is diluted with 75Tn! of cyclohexane, and after cooling, the crystallized substance is filtered with suction.Washing with a 1:1 mixture of diethyl ether and hexane gives 1
-(o-chlorobennol)-1H-1, 2.3-
Triazole-4,5-dicarboxylic acid trimethyl ester is obtained: melting point 88-91°. Example 15 1-(o-rioobenzyl-5-methoxy-II(-L
2,3-triazole-4-carboxylic acid 2.7 g (10
mmol) to thionyl chloride 15m/! Heat under reflux for 30 minutes. Excess thionyl chloride was distilled off under reduced pressure at 60°, leaving 1-(0-chlorobenzyl)-5-methoxy-IH-1.2. Dissolve 3-triazole-4-carboxylic acid chloride in toluene 20-. This toluene solution is added dropwise to a concentrated aqueous ammonia solution 20° at 0-5°. The precipitated product is filtered with suction and washed several times with water. 1-(0-Chlorobenzyl)-5-methoxy-II-1-1,2.3-)lyase 11,-4-carboxamide is obtained: melting point 185-187°. The starting material is prepared, for example, as follows: 0-chlorobenzyl azide 8,4,! in 25 Tnl of ethanol.
9 (5 CllJ mol) tomarone diethyl ester,
The mixture in which y (so mol) is dissolved is added to a solution of 1.15.9 (50 mmol) sodium in 50 ml of ethanol and the whole is left to stand at room temperature for 20 hours. Next, 10 to 10% of dimethyl sulfate 6,3p (50 mmol)
It is added dropwise at 20° and after 1 hour the whole is evaporated under reduced pressure at 25°. The residue is dissolved in ether acetate, washed with IN sodium hydroxide solution and then with water, and the whole is concentrated again by evaporation. The remaining oil is crystallized using 50 fnl of diethyl ether, melting point 118-12
1-(o-chlorobenzyl)-5-methoxy7-il (-i, 2.3-) lyazole-4-carboxylic acid ethyl ester having a 0° angle is obtained. 1-(o-chlorobenzyl)-5-methoxy-IH-1
, 33 g (11,2 mmol) of 2,3-triazole-4-carboxylic acid ethyl ester was dissolved in 507 g of warm ethanol.
After adding 15 rnl of IN sodium hydroxide solution, the mixture is heated under reflux for 1 hour. The precipitated sodium salt was further dissolved by adding 250 ml of water, and then 1 ml of 2N hydrochloric acid was added to dissolve the precipitated sodium salt.
Acidify with 5 ml. The precipitated product is filtered off with suction and washed with water. This gives 1-(o-chlorobennor)-5-methoxy-IH-1,2,3-)lyazole-4-carboxylic acid with a melting point of 130-135 DEG (relaxation/lz oxylation). Example 1b 6.4 g (27 mmol) of 1-(o-chlorobennor)-LH-1,2,3-triazole-4-carboxylic acid are heated under reflux for 1 hour with 50 ml of thionyl chloride. Next, excess thionyl chloride was distilled off under reduced pressure to remove the remaining 1-(
Dissolve o-chlorobenzyl)-1H-1,2,3-triazole-4-car4-'oyl chloride in 50 d of toluene, and add 5 to 1 oz of this solution to a concentrated ammonia aqueous solution 507.
True at 0. The precipitated product is filtered off with suction, washed with water and recrystallized from dioxane/ethanol. This gives 1-(o-chlorobenzyl LH-1,2,34 lyazole-4-carboxamide with a melting point of 237-239°. By a similar method, 1-(0-
rioobenzyl)-1H-1,2,3-triazole-
5-carpoxyamide can also be obtained. The starting material is produced, for example, as follows. A solution consisting of 16.75.9 g (100 mmol) of 0-chlorobenzyl azide, 7.35 g (100 mmol) of propynecarboxylic acid and 200 g of toluene was
Stir at 0° for 24 hours. After cooling to room temperature, the precipitated product is filtered off with suction and washed first with toluene and then with gelatin ether. This gives it a melting point of 175° (decomposition). ■-(o-chlorobenzyl)-1H, -1,2,
3-) Riazole-4-carboxylic acid is obtained. When the tear fluid is evaporated and concentrated and the residue is washed with a small amount of toluene, 1-(o-chlorobenzyl)-1 with a melting point of 120° (decomposition) is obtained.
H-1,2,3-)riazole-5-carboxylic acid remains. Example 17 1-(o-chlorobennor)-5-methyl-IH-1,
2,3-) Riazole-4-carboxylic acid 25,2.9(
A mixture of 100 mmol) and 100 M thionyl chloride is heated under reflux for 30 minutes. Excess thionyl chloride was then removed under reduced pressure and the remaining ]-(o-chlorobenzyl)-5-
Methyl-IH-1,,2°3-triazole-4-caldenoyl chloride is dissolved in 100 ml of toluene. This solution is poured into 100 ml of concentrated aqueous ammonia solution at 5 DEG to 10 DEG, and the precipitated product is filtered with suction and washed with water. When crystallized from ethanol, 1-(o-chlorobenzyl)-
5-Methyl-IH-1,2,3-triazole-4-carboxamide (melting point 181-183°) is obtained. The starting material is prepared, for example, as follows: 14.3 y of ethyl acetoacetate and 16.8 g (1,00 mmol) of 0-chlorobenzyl azide are mixed with 2.5 g of sodium chloride.
3. @(110 mmol) is ethanol 100 mA! and the whole is heated under reflux for 20 hours. After adding 100 ml of IN sodium hydroxide solution, the whole is heated under reflux for a further 2 hours. Then, while still warm, acidify with hydrochloric acid. The precipitated product is filtered off with suction and washed with water. When crystallized from ethanol, the melting point is 18
1-'(o-chlorobennor)-5-methyl-IH-1,2,3-triazole-4-carboxylic acid of 6 to 187° (decarboxylated) is obtained. Example 18 A solution of 14.7 g (100 mmol) of 0-methylbenzyl azide and 8.3 g (100 mmol) of buty-2-ynecarboxamide dissolved in 720 ml of dioxa was heated for 16 hours do. After evaporation of dioxane, the isomers are separated by column chromatography. This resulted in a melting point of 185-187° (ethanol)-1-(0-methylbenzyl)-5-methyl-IH-1.
, 2,3-triazole-4-carboxydiamide as well as by-products are obtained, the latter being discarded. Example 19 In a similar manner to Example 1, o-chlorobenzyl azide is reacted with 2-cyano-N-methylacetamide to give a
-amino-1-(o-chlorobenzyl)-1H-1,2
, 3-) lyazole-4-(N-methyl)-carxamide is obtained. Example 20 In a similar manner to Example 1, 0-chlorobenzyl azide is reacted with 2-cyano-N,N-trimethylacetamide to form 5-amino-1- with a melting point of 143-145° (from acetonitrile). (o-chlorobenzyl)-1H-
1,2,3-)lyazole-4-(N,N-dimethyl)
- A carboxamide is obtained. Example 21 When 2,3-dichlorobenzyl azide is reacted with cyanoacetamide by the same method as in Example 2, the melting point is 2.
5-amino-1- from 24 to 226° (from ethanol)
(2,3-dichloroben sol)-LH-1,2,3-
Triazole-4-carboxamide is obtained. The starting material is prepared by halogenating 2<3>-dichlorobenzyl alcohol as a raw material, for example using phosphorus tribromide, and reacting it with sodium azide. Example 22 Approximately 65% of crude 1-(o-chlorobenzyl)-IH-
1,2,3-1 riazole-4,5-dicardenoic acid trimethyl ester 10.4. F was suspended in 5 on Le of 4N ammonia methanol solution and the suspension was heated at 50° for 1
Stir for an hour. Cool the whole, filter with suction, and slowly dissolve 1-(o-chlorobenzyl)-11 in dioxane.
The (-1,2,3-)lyazole-4,5-dicarboxamide is eluted in the filter cake using dioxane. When the dioxane solution is concentrated and cooled, the compound precipitates in a crystalline form with a melting point of 222-224°. The starting material is prepared, for example, as follows: 1.15 g (50 mmol) of sodium in 100 ml of methanol.
dissolve in 1,2,3-triazole-4,5-1cal? 9.25 g (50 mmol) of phosphoric acid dimethyl ester and 8.05 g of 0-chlorobenzyl chloride. 1:50 mmol) is added to this and the whole is boiled for 24 hours. The reaction mixture is concentrated until crystallization begins, cooled and filtered with suction. The residue can be used without purification after drying. Example 23 In the same manner as in Example 6, using 21416-t'J methylbenzyl alcohol as the starting material, 2,
4. Melting point 195~ via 6-drimethylbenzole azide
5-amino-1,-(2
,4,6-)lyntylbenzyl)-IH-1,2,3-
) Riazole-4-carboxamide is obtained. Example 24 When 5-chloro-2-methylbenzyl alcohol is used as a starting material in the same manner as in Example 6, it becomes 5-chloro-2-methylbenzyl azide with a melting point of 247-24.
5-amino-1-(5-chloro-2) at 8° (from acetic acid)
-methylbenzyl)-IH-1,2,3-triazole-4-carboxamide is obtained. Example 25 In a similar manner to Example 1, using O-chlorobenzyl azide and piperidine cyanacetate as starting materials, 5 with a melting point of 138-140° (from ethanol) is prepared.
-amino-1-(0-chlorobenzyl)-1H-1,2
, 3-triazole-4-carboxylic acid piperidide is obtained. Example 26 In a similar manner to Example 2, using m-chlorobenzyl chloride as the starting material, 5-chlorobenzyl azide with a melting point of 196-198° (from ethanol)
-amino-1-(m-chlorobenzyl)-1H-1,2
, 3-1 riazole-4-carboxamide is obtained. Example 27 Using m-trifluoromethylbenzyl chloride as a starting material in the same manner as in Example 2, m-trifluoromethylbenzyl anode was used to form a compound with a melting point of 206 to 20.
5-Amino-1-(m −1 ) at 7° (from ethanol)
-lifluoromethyl)-1H-1,2,3-)lyazole-4-carboxamide is obtained. Example 28 In the same manner as in Example 16, 1-(0
-chloropennor)-1,H-1,2,3-triazole-4-carboxylic acid (11.8 g (50 mmol)) was converted to the acid chloride, and the acid chloride was treated with piperinone (50 mmol). , melting point 141-14
2° (from ethanol) of 1-(o-rioo penz/l
/)-1H-11213-triazole-4-carboxylic acid picklide is obtained. Furthermore, when the acid chloride was treated with dimethylamine (50 mmol), the melting point was 120 mmol.
1-(O-chlorobenzyl)-LH-1,2,3-triazole-4-caldenic acid N,N-tumethylamide of ~121° (from ethanol) is obtained. Example 29 In a similar manner to Example 1, using m-methylbenzyl anodide as the starting material, 5-amino-1-(m-methylbenzyl)-1H with a melting point of 200-202° (from ethanol) is produced. -1,2,3-triazole-4-carboxamide is obtained. Example 30 Using m-chlorobenzyl azide as the starting material in the same manner as in Example 16, the melting point was 174-176° (
1-(m-chlorobenzyl)-1H-1,2,
Melting point 223~ via 3-triazole-4-carboxylic acid
224° (from ethanol) 1-(m-rioobenzyl)-LH-1,213-triazole-4-carboxamide is obtained. Example 31 Using m-trifluoromethylbenzyl azide in the same manner as in Example 16, a
-(m-)lifluoromethylbenzyl)-1H-1,2
, 3-triazole-4-carboxylic acid, melting point 19
1-(m-)lifluoromethylbenzyl)-1H-1,2,3-triazole-4-carboxyamide of 3-195° (ethanol color) is obtained. Example 32 In the same manner as in Example 1, 0-chlorobenzylate and (4-methyl)cyanoacetic acid-piperazide are reacted to form 5-amino-]- having a melting point of 114-116°.
(]0-Chlorobenzyl-1H-1,2,3-)riazole-4-carboxylic acid (4-methylbenzyl) is obtained. Methanesulfonate melts at 208-210' (from acetone). Example 33 10.1 g of 5-amino-1-(o-chlorobenzyl)-1H-triazole-4-carboxamide was added portionwise to a mixture of 30.19 acetic anhydride and 0.1 ml sulfuric acid with stirring, Heat to 6o0. 30 more
Stirring is continued at 60-70° for minutes and the reaction mixture is poured into 250 d of ethanol, heated under reflux for 30 minutes and evaporated to dryness under reduced pressure. The residue is triturated with 250 ml of ethyl acetate, the crystalline precipitate is collected and recrystallized from ethyl acetate to give 5-acetylamino-
1-(o-chloropennor)-1H-1,2,3-)lyazole-4-carboxamide is obtained. The ethyl acetate mother liquor is collected and evaporated to dryness. The residue is purified by chromatography on silica gel and toluene/ethyl acetate. The eluate was evaporated to dryness and recrystallized from toluene to give 5-acetylamino-1-(o-chlorobenzyl)-1H-1,2,3 with a melting point of 140-142°.
4-lyazole-4-(N-acetyl)carboxamide is obtained. Example 34 In a similar manner as shown in Examples 1 to 33, the following compound is obtained: 1-(o-chloro4ndyl)-5-formylamino I
H-1,2,3-triazole-4-carboxamide], -(0-chlorobenzyl)-5-formylamino-IH-1,2,3-triazole-4-(N-formyl)-carboxamide 1 -(o-chlorobenzyl)-5-ethoxycarbonylamino-IH-1,2,3-)lyazole-4-carboxyamide 1-(o-chlorobennor)-s-(3,3-dimethylureido)-1H- 1,2,3-triazole-4-carboxamide 1-(o-chlorobennor)-5~(N', N'-
dimethylglycylamino)-LH-1,2,3-triazole-4-carboxamide 1-(o-chlorobenzyl)-5-ethoxyacetylamino-IH-1,2,3-)lyazole-4-carboxamide ]-(0-chlorobenzyl)-5-(4-methy/l/
e < 7) Nocarbonylamine/)-LH-1,2,
3-Triazole-4-carboxamide Example 35 5-amino-1-(o-methylbenzyl) -1H-1
,2,3-triazole-4-carboxamide 50~
Tablets each containing the following are manufactured, for example, as follows: Formulation (1000 tablets) Active ingredient 500.0g Lactose 500.0g , Og yam starch 352.0g gelatin
S, Og talc
60. ]j;'Magnesium stearate 10.0g silica (high dispersion)
2o, og ethanol
Drops The active ingredient is mixed with lactose and potato starch 292I, the mixture is moistened with an alcoholic solution of gelatin and granulated through a sieve. After drying, the whole was mixed with the remaining Yaca yam starch, talc, magnesium stearate and highly dispersed silica, and the mixture was compressed to a weight of 145.07719 lbs.
to form tablets containing 50.0 cm of active ingredient. If desired, these tablets may be provided with a break notch for precise control of dosage. Example 36 each 5-7 mi/-1-(o-methylbenzyl)-I
Glazed tablets containing 100 μm of H-1,2,3-triazole-4-carboxamide are produced, for example, as follows: Composition (1000 tablets) Active ingredients ioo, oog Lactose 100.00 g Corn starch 70 .00 g talc
8.50g Calcium stearate 1.50.9 Hydroxypropyl methylcellulose 2.36.9 Sierra
0064,9 Wed
Suitable for needle-based methylene
Mix an appropriate amount of active ingredients, lactose and 40.9 g of corn starch, and add 1.5 g of corn starch.
and moistened with a paste made from water (while heating) and granulated. Dry the granules and add corn starch residue, talc and calcium stearate and mix with the granules. Compress the mixture into tablets (weight 2 somp)
The tablets are lacquered using a solution of hydroxynorobyl methylcellulose and shellac in methylene chloride. The final weight of the polished tablet is 283 m9. Example 37 By a method similar to Examples 35 and 36, rolled tablets or glazed tablets containing the compound described in any of Examples 1 to 32 can be produced. EXAMPLES The compound of Example 11 can also be prepared differently as follows: Sodium 115I is dissolved in 5 Q ml of ethanol. A mixture of 3.3 g of 0-chlorobenzyl azide s,4y<malodinitrile and 50 rnl of ethanol is then added, and the whole is simmered at room temperature for 2
After standing for 4 hours, the solvent was distilled off under reduced pressure. The residue is treated with 2Ni acid 5
0 ml and 100 rnl of ethyl acetate, the organic phase is separated and concentrated by evaporation. The residue is recrystallized twice from ethanol. By this method, melting point 174-1
A 5-amino-1-(o-chlorobenzyl)-LH-1,2,3-1 lyazole-4-carboxylic acid nitrile having an angle of 76° is obtained. Patent applicant ChipperGeigy Akchenkaeselschaft Patent agent Akira Aoki Patent attorney Kazuyuki Nishidate Patent attorney Yukio Uchida Patent attorney Akira Yamaguchi Masaya Nishiyama

Claims (1)

[Claims] ■Primary formula II H1R2 (wherein ph represents a phenyl group substituted with lower alkyl, a halodane atom and/or a trifluoromethyl group, atk represents a lower alkylidene group, and R1 represents hydrogen) R2 represents an atom, a lower alkyl group or a lower alkoxy group, or an amino group or a carbamoyl group unsubstituted or polysubstituted by an acyl, lower alkyl or lower alkylene group or by an aza-, oxa- or thia-lower alkylene group; represents a carbamoyl group unsubstituted or substituted by an acyl, lower alkyl or lower alkylene group or by an azo-, oxa- or thia lower alkylene group, or R1 is unsubstituted or substituted by an acyl, lower alkyl or lower alkylene group or by an azo-, oxa- or thia-lower alkylene group; -, oxa- or thia.When it represents an amino group substituted by a lower alkylene group, it represents a cyano group; or 1-phenyl-lower alkyl-IH-1, represented by (1-phenyl-lower alkyl-IH-1)
A 2,3-t'7 azole compound or a salt of a salt-form acid compound represented by formula (1). 2. In formula I, Ph is substituted in the 2-position by a lower alkyl group, a halodane atom or a trifluoromethyl group, optionally in the 3-24- or 6-position, preferably 3-i! or further # with a lower alkyl group or a halodane atom at the 6th position
represents an optionally substituted phenyl group, atk represents a lower alkylidene group, R1 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or an amine group or carbamoyl group unsubstituted or substituted with a lower alkyl group; , R2 represents a carbamoyl group which is unsubstituted or substituted with a lower alkyl group, or a cyan group when R1 represents an amine group which is unsubstituted or substituted with a lower alkyl group, Claim 1 Compounds described. 3. In formula f, ph represents a lower alkyl group, a phenyl group substituted with a halodane atom and/or a trifluoromethyl group, atk represents a lower alkylidene group, and R1 represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group. , amino group, acylamino group, N-i class alkyl-1
N, N-no lower alkyl-11'J, N-lower alkylene or N. N-(azo-, oxa- or thia)-lower alkylene-amino group, carbamoyl group, N-acylcarbamoyl group or N-lower alkyl-, N rN-no-lower alkyl-1N, N-lower alkylene- or N, N-
(aza, oxa or thia)-lower alkylene-
represents a carbamoyl group, R2 is a carbamoyl group, N-
Lower alkyl-,N,N-No lower alkyl-1N,N
-lower alkylene- or N, N-(aza-, oxa-moshikakethia)-lower alkylene-carbamoyl group, or R1 is an amine group, an acylamino group, N
-Lower alkyl-, N IN-No lower alkyl-, N
, N-lower alkyleno- or N,N-(azo-, oxa- or thia)-lower alkylene-ami7 group represents a cyano group, and R4 is carbamoyl4, N-acylcarbamoyl group, N -(11furkyl-1N, N-no-lower alkyl-1N, N-lower alkylene- or N,N-(azo-, oxa- or thia)-lower alkylene- When a carbamoyl group is represented, a hydrogen atom or lower alkyl group, provided that the acyl group is a lower alkanoylamino group having up to 7 carbon atoms,
Lower alkamyl group, lower alkoxy-alkanoyl group, no-lower alkylamino-lower alkanoylalkanesulfonyl group, low M alkoxycargonyl group, ureido group, 3-lower alkyl group or 3,3-no lower alkylureido group, 3,3- Lower alkylene ureido group or 3, 3- (azo-, oxa- or thia)
- means a lower alkylene ureido group, including a lower alkyl group, a 1st class alkyl group in an N-lower alkyl-amino or -cal-gumoyl group, a N,N-di-lower alkyl-aminomodicyl group, a lower alkokene group and a lower alkyl group; A nodene group has, for example, up to 7 carbon atoms, and a lower alkylene group or an azo-, oxa- or thia-lower alkylene group is, for example, a compound having from 4 to 6 hard ring members or as defined above. The compound according to claim 1, which is a salt of a salt-forming compound of a silkworm. 4. In the formula l, ph is a 2-no-lophenyl group, 2-trifluoromethylphenyl M, 2-low M7 rukylphenyl-g, 2.3-also l, (is a 2,6-nono-10 phenyl group) , 2-halo 3 (Jl & alkylphenyl group 4
L<c:U1]・low 2-low u alkylphenyl 2,
represents a 3- or 2,6-no-lower alkylphenyl group, a 2-no-3-trifluoromethylphenyl group, or a 2-no-6-)lyfluoromethylphenyl group, and ark represents a 1,1-lower alkylidene group; R1 is an aqueous atom, a lower alkyl group, a lower alkoxy group, an amino group, a lower alkylamino group, a non-lower alkylamino group, a carbamoyl group, an N-lower alkyl carnogumoyl group, or an N,N-less lower alkyl group; R2 represents a carbamoyl group, N-lower alkylcarbamoyl group or N,N-no-lower alkylcarbamoyl group, and R2 represents a lower alkyl group and an N-lower 1-rukylamino or -carbamoyl group (ikN alkyl The lower alkyl group of the group ν and the N,N-di-lower alkylamino- or -carbamoyl group, as well as the lower alkoxy group and the lower alkylidene group, are compounds having up to 71 carbon atoms, as claimed in claim 2. 5. In formula 1, ph represents a lower alkyl group or a phenyl group substituted by up to 3 halocarbon atoms and/or a trifluoromethyl group, provided that the lower alkyl group has up to 4 carbon atoms. , the halogen atom is one with an atomic stack of 35 or less, and atk is 4 carbon atoms.
1,1-lower alkylidene group, R4 is an amino group, a lower alkanoylamino group having up to 7 carbon atoms, a lower alkylamino group or no lower alkylamino group in which each lower alkyl moiety has up to 4 carbon atoms; , R2 is a carbamoyl group, N having 7 or less carbon atoms
- lower alkanoylcarbamoyl group, each lower alkyl moiety having up to 41 carbon atoms, lower alkyl τ, N, in which the lower alkylene moiety has 4 to 6 loam-forming members;
16. Compound 16 according to claim 1, which represents an N-no-low iron alkyl group, an N, N-lower alkyleno-carbamoyl group, or a cyano group. 6. In formula I, ph represents 2-halophenyl, 2-lower alkylphenyl, 2,3- or 2゜6-nohalophenyl, or 2,3- or 2,6-no-lower alkylphenyl group 2, provided that halogen substitution The group is a rhodane atom with an atomic number of up to 35, the lower alkyl substituent has up to 4 carbon atoms, or ph represents a 2-trifluoromethylphenyl group and atk is 1.0 with up to 4 carbon atoms. 1-lower alkylidene group, R1 represents an amine group, each lower alkyl moiety represents a lower alkylamino group or no lower alkylamino group having up to 4 carbon atoms, and R2 represents a carbamoyl group. Compound according to item 2. 7.5-amino-1-(o-chlorobenzyl)-IH-
The compound according to claim 1, which is 1,2,'3-)reaze-ru-4-calgexamide. 8.5-Amino-1-(2,6-sochloropenol)-
1) I-1,2,3-triazole-4-ka111?
xyamide. 5-amino-1-(o-methylpennol)-1[(-1
,2,3-triazole-4-carboxamide. 5-amino-1-(o-fluorobenol)-IH-1
, 2,3-triazole-4-carbomodiamide. 5-amino-1-(o-bromopenol)-1H-1,
2,3-) Riazole-4-carboxamide. 5-7mi/-1-(o-)lifluoromethylbenzyl)
-1H-1,2,3-)lyazole-4-carboxamide. 5-amino-1-(2,3-trimethylbenzyl)-11
-I-1,2,3-triazole-4-carboxamide. 5-amino-1-(1-(o-chlorophenyl)-ethyl)-1H-1,2,3-triazole-4-carxamide. 5-amino-1-(1-(o7chlorophenyl)-zorobyl-IH-1,2,3-)lyazole-4-carboxamide. 5-amino-1-(1-(ti-chlorophenyl)-butyl)-1H-1,2,3-)lyazole-4-hydrudexamide. 5-Amino-1゛2(d-chlorophenyl)-1H-1
,2,3-)lyazole-4-carboxylic acid nitrile
. 1-(d-chlorobenzyl)-5-dimethylamino-1
t(-1,2,3-)lyazole-4-carboxylic acid nitrile. 1-(b-chlorobenzyl)-5-dimethylamino-I
H-1,2,3-) lyazole-4-carboxamide. 1-(a-rioobenzyl)-1H-1,2,3-triazole-4,5-nocarboxyamide. 1-(0-chlorobenzyl)-5-)I-xyLH-
1,2,3-triazole-4-carboxamide. 1-(i>-Chlorobenol)-1H-1,2,3-triazole-4-carboxyamide. 1-(.-chlorobenzyl)-5-methine l/-IF(
-1,2,3-triazole-4-carboxamide. 1-(.-methylbenzyl)-5-methyl-IH-1,
2,3-triazole-4-carboxamide. 5-Amino-I-(6-chlorobennor)-1[f-1
,2,3-1 lyazole-4-(N-methyl)-carboxyamide. 5-amino-1-(o-chlorobennor)-LH-1,
2,3-1 lyazole-4-(N,N-tumethyl)-cardoxyamide. 5-amino-1-(2,3-sochloropensol)-11
(-1,2,3-triazole-4-carboxamide. 5-amino-'-(2e4*6-trimethylbenzyl)-1H-1,2,3-triazole-4-carboxamide. 5-amino- 1-(5-chloro-2-methylpennol)
-1H-1,2,3-triazole-4-carboxamide. 5-Amino-1-(o-chlorobennor) -i t+
-1,2,3-triazole-4-carboxylic acid piperinod. 5-amino-1-(m-chlorobennol)-in-1,
2,3-) Riazole-4-carboxamide. 5-Amino-1-(m-trifluoromethylpennol)
-1H-1,2,3-1 lyazole-4-carboxamide. ■-(o-rioobenji/L/) -1H-1, 2, 3
-triazole-4-carboxylic acid piperinod. 17 (o-rioobenzyl)-1H-1,2,3-triazole-4-cal month? acid N,N-trimethylamide. 5-Amino-1-(m-methylbenol) -1f(-
1,2,3-triazole-4-carboxamide. 1-(m-rioobenzyl)-1[(-1,2,3-triazole-4-carboxamide. 1-(m-)'Jfluoromethylpennol)-L[(
-1,2,3-) lyazole-4-carboxamide. 5-amino-1-(o-chlorobennor)-LH-1,
2,3-triazole-4-car22noic acid (4-methyl)-1:''-'8! Rudd or its acid addition salt. 5-acetylamino-1-(o-chlorobenzyl)-1
H-1,2,3-) Riazole-4-carboxamide. 5-acetylamino-1-(o-chlorobenzyl)-1
H-1,2,3-triazole-4-(N-acetyl)
Carboxamide. 1-(o-chlorobenzyl)-5-formylamino-1
1(-1,2,3-triazole-4-carboxamide. 1-(o-chlorobenzyl)-5-formylamino-I
H-1,2,3-triazole-4-(N-formyl)
Carboxamide. 1-(o-chlorobenzyl)-5-ethoxyl-nylamino-IH-1,2,3-)lyazole-4-carxamide. 1-(o-chlorobennor)-5-(3,3-trimethylureido)-1f(-1,2,3-triazole-4-
Carboxamide. 1-(o-chlorobenzyl)-5-(N',N'-nomethylglyzylamine)-1f(-1,2,3-)lyazole-4-carboxinamide. 1-(o-chlorobenzyl)-5-ethoxyacetylamino-1f(-1,2,3-) lyazole-4-carboxyamide or 1-(o-chlorobenzyl)-5-(4-methylvinylbenzinocarboxylamino) )-XH-1,2°3-triazole-4-carboxyamide. The compound according to claim 1, which is 9. Together with the auxiliary agents and/or carriers commonly used in formulations, the following formula (■): R, R2 (wherein ph is a phenyl group substituted with lower alkyl, haloke "'/atom and/or trifluoromethyl group) , atk represents a lower alkyl group, R1 is a hydrogen atom, a lower alkyl group or a lower alkoxy group, or an unsubstituted or acyl, lower alkyl or lower alkylene group, or azo-, oxa- or thia-lower represents an amino group or a carbamoyl group substituted by an alkylene group, R2 represents a carbamoyl group unsubstituted or substituted by an acyl, lower alkyl or lower alkylene group or by an azo-, oxa- or thia lower alkylene group, or R is an unsubstituted acyl, lower alkyl or lower alkylene group, or azo-
, oxa-moshi7 or thia by a lower alkylene group i
When it represents a substituted amine group, it represents a cyano group, or a carbamoyl group in which R1 is unsubstituted or substituted by an acyl, lower alkyl or lower alkylene group or by an azo-, oxa- or thia-lower alkylene group. Is it a hydrogen atom or a lower alkyl group? represent ) 1-phenyl-lower alkyl-IH-1,
A pharmaceutical preparation comprising 2,3-1 lyazole. 10, the following formula I: 1Ft2 (in the formula, ph is lower alkyl) represents a phenyl group substituted with log/atom and /4 or a trifluoromethyl group, ark represents a lower alkylidene group, R1 is hydrogen represents an amino or carbamoyl group substituted directly by an atom, a lower alkyl group or a lower alkyl group, or an acyl, lower alkyl or lower alkylene group, or by an azo-, oxa- or thia-lower alkylene group; , R2 represents a carbamoyl group which is unsubstituted or substituted by an acyl, lower alkyl or lower alkylene group or by an azo-, oxa- or thia lower alkylene group; When R1 represents an amine group substituted by a lower alkylene group or by an aza-, oxa- or thia-lower alkylene group, it represents a cyan group, or if R1 is unsubstituted or substituted by an acyl, lower alkyl or lower alkylene group. Alternatively, when it represents a carbamoyl group substituted by an azo-, oxa- or thia-lower alkylene group, it represents a hydrogen atom or a lower alkyl group. ) 1-phenyl-lower alkyl-II (-1
Ph-ajk-N3 (II
) is represented by the following formula: 2Y3 (in the above formula, R2' is a cyan group or unsubstituted or substituted by an acyl, lower alkyl or lower alkylene group, or by an azo-, oxa- or thia-lower alkylene group) represents a carbamoyl group, Yl represents an amine group disubstituted by the above-mentioned group V, or it2' is unsubstituted or by an acyl, lower alkyl or lower alkylene group, or an azo-, oxa- or thia-lower alkylene group. Cal replaced by
When a moyl group is represented, it represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a carbamoyl group that is unsubstituted or substituted with the above group. represents a bond or R
2' represents a cyano group or a carbamoyl group which is unsubstituted or substituted by an acyl, lower alkyl or lower alkylene group or by an azo-, oxa- or thia lower alkylene group, Y and Y2 together represent an imino group; Y3 represents a hydrogen atom. ) or a tautomer thereof and/or a salt thereof; or the following formula ■: Ph -atk -Z (1%Q(
In the formula, 2 represents a reactive ester ratio hydroxyl group. ) is reacted with a It(-1,2,3-1-lyazole derivative or a salt thereof represented by the following formula V:c1) or a compound represented by the following formula (■): 5 (wherein Y4 represents a YA group, and Y5 is an R1 group or Y
Y4 represents R2 group and Y5 represents YB group.
group, provided that YA is a group that can be converted into an unsubstituted or substituted carbamoyl group as described above, or when Y5 represents an amino group R1 which may optionally be substituted as described above; represents a group that can be converted to a cyan group, and Y8 represents a group that can be converted to a carbamoyl group that may optionally be substituted as described above. ) or a salt thereof, YA is converted to a cyano group or a carbamoyl group optionally substituted as described above, and/or YB is optionally substituted as described above. Conversion to carnogmoyl group or lower margin
? H-Y6 is eliminated from a compound represented by the following formula ■: 6H (in the formula, Y6 represents a leaving group), or the compound represented by the following formula: f (in the compound represented by O, hydroxyl converting the group into a lower alkoxy group and, if necessary, separating the resulting exogenous compound into its components and isolating the isomer of formula I;
If desired, the compound obtained by the above method is converted into a different compound of formula I and/or into the free compound No. 4 obtained by the above method or the salt obtained by the above method. A method for producing compound 16 represented by the above formula (2), which comprises converting fr into a free compound.